We previously found that lymph node T cells from 4-day-old, naive neonatal mice show diminished Th1-like responses. Neonatal T cells produced low levels of IL-2 and proliferated poorly in response to soluble anti-CD3 stimulation. However, neonatal T cells resembled Th2 cells (or primed adult T cells) in that they produced large amounts of IL-4. Here, we have investigated the importance of accessory cell signals in the diminished Th1-like responses of neonatal T cells. Anti-CD28 mAb greatly augmented IL-2 production by neonatal T cells in response to plate-bound anti-CD3 Ab. In response to soluble anti-CD3 mAb plus accessory cells, exogenous accessory cell-derived cytokines were sufficient to restore neonatal responses to adult-like levels. In the presence of exogenous IL-6, IL-4 production by neonatal T cells was largely unchanged whereas IL-2 production was dramatically increased, reaching the high levels produced by adult T cells. In addition, the presence of exogenous IL-6 enhanced the proliferation of neonatal T cells to adult levels. IL-6 also had marked effects on the capacity of neonatal T cells to respond to secondary stimuli. In the absence of exogenous IL-6, neonatal T cells responded poorly to secondary stimulation. This lack of responsiveness was not overcome by the addition of IL-2 or by stimulation with phorbol ester and calcium ionophore. When IL-6 was present during the primary stimulation, neonatal T cells, like adult T cells, produced high levels of IL-4 and proliferated extensively in response to secondary stimuli. Thus, IL-6 was sufficient to restore both the primary and secondary responses of neonatal T cells to mature, adult-like levels. These results imply that neonatal T cells have a greater requirement for accessory cell signals than do adult T cells and may have important bearing in overcoming neonatal T cell immunodeficiencies in vivo.